From: "Anthe Zandvliet" Apaza@SLZ.NL
Subject: [NMusers] simulation of dose escalation study
Date: Fri, April 15, 2005 5:34 am
Dear all,
I want to simulate a dose escalation study based on a PKPD population model. With
the attached files, I can indeed perform the simulation. However, I need to redefine
the seed for each individual. Does anyone know how to perform this simulation in a
more automated manner?
The PKPD model (which I have simplified for the purpose of asking for your
recommendations) comes down to:
- a 1-compartment linear PK model. The drug is administered as a singel bolus at
time=1.
- a PD model representing a side effect of the drug.
- a dummy compartment to calculate the maximal side effect.
The maximal side effect is representative for the severeness of the side effect and
determines whether or not the dose is escalated. If the maximal side effect remains
below 50 in a particular patient (A), the dose for the subsequent patient (B) is
escalated to the next dose level. If the maximal side effect of patient A is larger
than 50, the dose for patient B remains at the same level. etc.
Using 006_1.ctl, the maximal side effect Emax is simulated for patient A.
Subsequently, 007.ctl is applied to determine the dose level for patient B. Emax of
patient B is determined with 006_2.ctl where the seed is changed from 1 to 2. Again,
007.ctl calculates the dose level for patient C. etc.
This can be done quite easily for a couple of patients using a batch file. However,
in order to simulate 200 studies of 20 patients each, 4000 control streams should be
renamed and seeds need to be changed.
Does anyone know how to do this more conveniently? Thank you in advance!
Best regards, Anthe
************************************
nmusers.for
SUBROUTINE READER()
COMMON /READ/ TID,TCOV
REAL TID(13),TCOV(13,2)
OPEN(UNIT = 77,FILE = 'DATA.CSV')
REWIND 77
DO 11,I = 1,13
READ(77,*) TID(I),TCOV(I,1), TCOV(I,2)
11 CONTINUE
END
SUBROUTINE GET_SUB(NEWIND,ID,CURID,COV1,COV2,MID)
COMMON /READ/ TID,TCOV
REAL ID,CURID,COV1,COV2,MID
INTEGER NEWIND
REAL TID(13),TCOV(13,2)
IF (NEWIND.EQ.1) THEN
12 CONTINUE
IF(ID.GT.TID(CURID)) THEN
CURID =CURID + 1
GOTO 12
END IF
ELSEIF(NEWIND.EQ.0) THEN
CURID = 1
END IF
COV1 = TCOV(CURID,1)
COV2 = TCOV(CURID,2)
MID = TID(CURID)
END
************************************
006.csv
SID ID TIME AMT LEV DV NUL
1 13 0 0 50 0 0
1 13 1 1 50 0 0
1 13 2 0 50 0 0
1 13 3 0 50 0 0
1 13 4 0 50 0 0
1 13 5 0 50 0 0
1 13 6 0 50 0 0
1 13 7 0 50 0 0
1 13 8 0 50 0 0
1 13 9 0 50 0 0
1 13 10 0 50 0 0
1 13 11 0 50 0 0
1 13 12 0 50 0 0
*****************************
006.bat
CALL NMFE5 006_1.CTL 006_1.RES
CALL NMFE5 007.CTL 007.RES
CALL NMFE5 006_2.CTL 006_2.RES
CALL NMFE5 007.CTL 007.RES
CALL NMFE5 006_3.CTL 006_3.RES
CALL NMFE5 007.CTL 007.RES
************************************
006_1.ctl
$PROB RUN# 006
$INPUT SID ID TIME AMT LEV DV NUL
$DATA 006.CSV IGNORE=@
$SUBROUTINES ADVAN6 TOL=5
$MODEL COMP=(PK, DEFDOS)
COMP=(PD, DEFOBS)
COMP=(EMAX)
$PK
F1=LEV
S1=THETA(1)*EXP(ETA(1))
K12=THETA(2)*EXP(ETA(2))
S2=THETA(3)*EXP(ETA(3))
K20=THETA(4)*EXP(ETA(4))
IF(TIME.EQ.0) CID=1
IF(TIME.EQ.1) CID=2
IF(TIME.EQ.2) CID=3
IF(TIME.EQ.3) CID=4
IF(TIME.EQ.4) CID=5
IF(TIME.EQ.5) CID=6
IF(TIME.EQ.6) CID=7
IF(TIME.EQ.7) CID=8
IF(TIME.EQ.8) CID=9
IF(TIME.EQ.9) CID=10
IF(TIME.EQ.10) CID=11
IF(TIME.EQ.11) CID=12
IF(TIME.EQ.12) CID=13
$DES
DADT(1)=-K12*A(1)
DADT(2)=K12*A(1)-K20*A(2)
IF(DADT(2).GT.0) THEN
DADT(3)=DADT(2)
ELSE
DADT(3)=0
ENDIF
$ERROR
IPRED=F
Y=IPRED*EXP(EPS(1))
E=A(2)/S2
EMAX=A(3)/S2
$THETA
1 ;S1
0.5 ;K12
1 ;S2
0.3 ;K20
$OMEGA
0.01
0.01
0.01
0.01
$SIGMA
0.01
$SIMULATION (1) ONLYSIM
$TABLE SID ID TIME AMT DV DV NUL
FILE=006.TAB NOAPPEND NOPRINT ONEHEADER NOFORWARD
$TABLE CID EMAX LEV
FILE=DATA.CSV NOAPPEND NOPRINT NOHEADER NOFORWARD
********************************
007.ctl
$PROB RUN# 007
$INPUT SID ID TIME AMT DVR DV NUL
$DATA 006.TAB IGNORE=@
$SUBROUTINES OTHER=NMUSERS.FOR
$PRED
" FIRST
" REAL CURID,ICOV1,ICOV2,MID
" LOGICAL READ
" IF(.NOT.READ)THEN
" CALL READER()
" CURID=1
" READ=.TRUE.
" ENDIF
" IF(NEWIND.LT.2)THEN
" CALL GET_SUB(NEWIND,ID,CURID,ICOV1,ICOV2,MID)
" ENDIF
COV1=ICOV1
COV2=ICOV2
EMAX=ICOV1
LEV=ICOV2
IF(LEV.EQ.50) NEXT=100
IF(LEV.EQ.100) NEXT=200
IF(LEV.EQ.200) NEXT=400
IF(LEV.EQ.400) NEXT=500
IF(LEV.EQ.500) NEXT=600
IF(LEV.EQ.600) NEXT=700
IF(LEV.EQ.700) NEXT=800
IF(LEV.EQ.800) NEXT=1000
IF(LEV.GE.1000) NEXT=LEV+100
IF(EMAX.GT.50) THEN
LEVN=LEV
ELSE
LEVN=NEXT
ENDIF
SIDN=SID+1
X=THETA(1)*EXP(ETA(1))
Y=X
$THETA
1
$OMEGA
0.0001
$SIMULATION (9999) ONLYSIM
$TABLE SIDN ID TIME AMT LEVN NUL NUL
FILE=006.TAB NOPRINT ONEHEADER NOFORWARD
$TABLE SID ID TIME LEV EMAX DVR
FILE=007.TAB NOPRINT ONEHEADER FORWARD
**********************************
006_2.ctl
;Model Desc: base model
;Project Name: pkpd simulaties
;Project ID: NO PROJECT DESCRIPTION
$PROB RUN# 006
$INPUT SID ID TIME AMT LEV DV NUL
$DATA 006.TAB IGNORE=@
$SUBROUTINES ADVAN6 TOL=5
$MODEL COMP=(PK, DEFDOS)
COMP=(PD, DEFOBS)
COMP=(EMAX)
$PK
F1=LEV
S1=THETA(1)*EXP(ETA(1))
K12=THETA(2)*EXP(ETA(2))
S2=THETA(3)*EXP(ETA(3))
K20=THETA(4)*EXP(ETA(4))
IF(TIME.EQ.0) CID=1
IF(TIME.EQ.1) CID=2
IF(TIME.EQ.2) CID=3
IF(TIME.EQ.3) CID=4
IF(TIME.EQ.4) CID=5
IF(TIME.EQ.5) CID=6
IF(TIME.EQ.6) CID=7
IF(TIME.EQ.7) CID=8
IF(TIME.EQ.8) CID=9
IF(TIME.EQ.9) CID=10
IF(TIME.EQ.10) CID=11
IF(TIME.EQ.11) CID=12
IF(TIME.EQ.12) CID=13
$DES
DADT(1)=-K12*A(1)
DADT(2)=K12*A(1)-K20*A(2)
IF(DADT(2).GT.0) THEN
DADT(3)=DADT(2)
ELSE
DADT(3)=0
ENDIF
$ERROR
IPRED=F
Y=IPRED*EXP(EPS(1))
E=A(2)/S2
EMAX=A(3)/S2
$THETA
1 ;S1
0.5 ;K12
1 ;S2
0.3 ;K20
$OMEGA
0.01
0.01
0.01
0.01
$SIGMA
0.01
$SIMULATION (2) ONLYSIM
$TABLE SID ID TIME AMT DV DV NUL
FILE=006.TAB NOAPPEND NOPRINT ONEHEADER NOFORWARD
$TABLE CID EMAX LEV
FILE=DATA.CSV NOAPPEND NOPRINT NOHEADER NOFORWARD
Slotervaart Hospital
Dept. Pharmacy and Pharmacology
Louwesweg 6
1066 EC AMSTERDAM
The Netherlands
Telephone +31 20 512 4657
FAX + 31 20 512 4753
simulation of dose escalation study
From: "Tsai, Max" max.tsai@spcorp.com
Subject: RE: [NMusers] simulation of dose escalation study
Date: Fri, April 15, 2005 8:07 am
Anthe,
I have encountered a similar issue recently. There are two approaches that
I have taken. The first approach utilizes a programming language (I used
SAS) to create all of the control streams to be run in your simulation.
Using a "random" number generator, specify the random value as part of a
larger character string (i.e. control stream) in SAS so that each control
stream will have a different seed value. The second approach uses the
subproblem option of the simulation statement in NONMEM. In your case,
subproblems=200. This should provide different values for each replicated
study. You may need to use SAS or some other software to help you sort
through what will be a large output table. Hope this helps.
-Max
From: "Anthe Zandvliet" Apaza@SLZ.NL
Subject: RE: [NMusers] simulation of dose escalation study
Date: Fri, April 15, 2005 8:22 am
Dear Max,
Thank you for your prompt response. The application of SAS sounds like a solution to
the problem. I have never used it, though, and was hoping to find a solution within
nonmem. The subproblems option doesn't work in this particular case, because 2
control streams are required to simulate data for 1 individual.
Regards,
Anthe
From: "Leonid Gibiansky" leonidg@metrumrg.com
Subject: RE: [NMusers] simulation of dose escalation study
Date: Fri, April 15, 2005 9:29 am
Anthe,
Design of the study is not completely clear from your e-mail (whether you do
escalation for all 20
volunteers or you block them by cohorts) and I have not tested it before but: you
may be able to do
it using
$ABBREV COMRES=
option. COMRES allows you to store and use global variables that are transfered from
one time to the
next one and from the volunteer to the next volunteer. Using few COM(.) variables,
you may be able
to create an indicator whether previous volunteer had adverse event (and the next
dose should be
equal to the previous one) or dose needs to be increased. Dose increase can be done
via
bioavailability parameter F. In your data file you assign initial (equal) doses for
all 20 patients
but increase F if needed (if COMRES-stored variables dictate you to do so).
The control stream / data file should describe a study of 20 volunteers. The you can
use
SUBPROBLEMS=200 options to repeat it 200 times.
Leonid
From: "Anthe Zandvliet" Apaza@SLZ.NL
Subject: RE: [NMusers] simulation of dose escalation study
Date: Fri, April 15, 2005 10:53 am
Leonid,
Thank you very much for your helpful input! I will indeed cluster the volunteers in
cohorts, but I had reduced the control stream to a minimum length for the purpose of
sending it to NMUsers.
Anthe
From: mark.e.sale@gsk.com
Subject: RE: [NMusers] simulation of dose escalation study
Date: Mon, April 18, 2005 12:23 pm
Anthe,
The simulation seed can be accessed in the FCON file, which can be editted by a number of
methods, in the line SORC. This can be easily edited using macros (I prefer Excel, very
easy to write) Then, you don't have to recompile NONMEM, just run the executable again.
(I'll be happy to share code on how to do this if needed) Here is an FCON from simulation.
FILE FSTREAM
PROB example
DATA 1 0 0 10 0
ITEM 1 3 10 11 1 0 0 0 0 0 20 0 0
INDX 9 2 4 0 5 6 8 0 0 0 7
LABL ID TIME DV AMT SS II ADDL CMT EVID
MDV
IOB
VC LC
FORM
(9E5.0,1F2.0)
STRC 6 5 1 0 0 0 4 1 0
STRC 1 1 1 1 1 2 1 1
THCN 1 0 0 0
THTA .0167 83.7 0.651 1.33 1.16 0.0034
LOWR 0 0 -2 0-1000000 0
UPPR 1000000 1000000 1 1000000 1000000 1000000
BLST 0.0807
BLST 0.041
BLST 0.0829 -.0631 0.133
BLST 0.583
DIAG 1 0
SIML 0 1 0 0 1 0 0
SORC 061997622 0
TABL 1 2
TABL 1 4 1 0 2 0 30 0 9 0
0 1 1 0 0
TABL 1 4 1 0 2 0 32 0 33 0
0 1 1 0 1
And here is some simple Excel macro code to edit it with a new simulation seed
Public Sub set_fcon()
DoEvents
Open "fcon" For Input As #1
Open "fcon.new" For Output As #2
Dim line As String
While Not EOF(1)
Line Input #1, line
If Left(line, 4) <> "SORC" Then
Print #2, line
Else
Print #2, "SORC " & Format(Rnd() * 100000000, "000000000") & " " & 0
End If
Wend
Close #1
Close #2
FileCopy "fcon.new", "fcon"
End Sub
Mark Sale M.D.
Global Director, Research Modeling and Simulation
GlaxoSmithKline
919-483-1808
Mobile
919-522-6668
_______________________________________________________